The present invention relates to novel peptide derivatives, their preparation process and their pharmaceuticals. More specifically, it relates to peptide derivatives of pentagastrin more particularly usable as antagonists to gastrin and "related polypeptides".
It is pointed out that gastrin is a natural hormone, more particularly known as being responsible for the secretion of gastric juice. Its manner of acting on the organs of the digestive system, like that of most hormones, is linked with the presence in said organs of target cells, whose plasma membranes have specific biological receptors able to fix the hormone molecules and, under the action of the latter, produce a cascade of biochemical reactions leading to the production of a specific product, such as hydrochloric acid.
The term "related polypeptides" is used to describe a group of polypeptides having at their C-terminal end the sequence of four amino acids: L-tryptophanyl-L-methionyl-L-aspartyl-L-phenylalanine amide, characterizing the biological activity of gastrin. These polypeptides are also able to produce biochemical reactions by fixing to specific receptors.
It is known that a hormonal hypersecretion can lead to certain known pathological problems, e.g. for gastrin, during the Zollinger-Ellison syndrome and are also suspected in numerous other ailments.
Over the past few years, research has been directed at the preparation of compounds able to inhibit gastric secretions. To this end, polypeptides have been proposed, which act as antagonists to pentagastrin, such as compounds of formula A-W-X-Asp-Y-NHR, in which A is hydrogen, an alkanoyl group with 2 to 6 carbon atoms, a succinyl group, t-butoxycarbonyl, benzyloxycarbonyl, D-pyroglutamyl or L-pyroglutamyl; W is the tryptophanyl or D-tryptophanyl radical; X is the methionyl, D-methionyl, norleucyl or D-norleucyl radical; Y is a radical of formula: ##STR2## in which R' is an alkyl radical in C.sub.1 to C.sub.6, or an alkyl or cycloalkyl radical in C.sub.6 to C.sub.7, or of formula: ##STR3## and R is hydrogen or an alkyl radical in C.sub.1 to C.sub.6.
In these polypeptides, e.g. N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine amide the replacement of the L-phenylalanyl radical of the sequence of the four amino acids of gastrin by the radical: ##STR4## makes it possible to obtain this inhibiting effect (cf U.S. Pat. No. 4,012,367 of Robert H. Mazur).
For the inhibition of gastric secretion, use has also been made of polypeptides having the sequence of the four amino acids of gastrin, but whose tryptophanyl residue has been replaced by the orthonitrophenylthio radical, as described in French Pat. No. 2,364,659, filed on 21.9.1976, in the name of the Commissariat a l'Energie Atomique and INSERM. Thus, hitherto, it has been possible to obtain this gastric secretion inhibiting effect, either by modifying the characteristic sequence of the four amino acids of gastrin, or by substituting the tryptophanyl residue of said sequence.
As a result of further research, it has now been found that an inhibiting effect can also be obtained by modifying the aspartyl residue of the sequence of the four amino acids of gastrin.